In response to pathophysiologic stress or disease the adult heart undergoes hypertrophic enlargement such as concentric remodeling where individual adult cardiomyocytes primarily thicken. The heart can also undergo substantial dilation with more eccentric remodeling in response to different or progressive disease states in which myocytes more exclusively lengthen. These disease states involve neuroendocrine regulatory circuits initiated at the sarcolemma through G-protein coupled-receptors and receptor tyrosine kinases that in turn activate intermediate signal transduction pathways such as mitogen-activated protein kinases (MAPK). Previous literature indicates that each of the three major MAPK signaling branches (extracellular signal-regulated kinases [ERKs], c-Jun N-terminal kinases [JNKs] and p38) act as important regulators of cardiomyocyte growth dynamics. The myocyte itself is also thought to sense tension and/or stretch which can also initiate signal transduction, such as through the MAPK pathways to regulate growth. Past funding of this award focused on how MAPK signaling through GATA4/5/6 transcription factors regulated cardiac growth or dilation. We also previously showed that MEK1-ERK1/2 signaling specifically controls the decision of an adult cardiomyocyte to grow in width versus length. Here we propose an innovative renewal of this 19 year running award to mechanistically examine how myocytes respond to their environment and decide to grow in width versus length, and how this then impacts the remodeling of the entire 3-dimensional heart as either concentric or dilatory growth, such as in the familial hypertrophic (HCM) and dilated cardiomyopathies (DCM). Our 3 specific aims are 1) to define the cellular and molecular dynamics of MEK1-ERK1/2 in the heart and identify potential novel effectors of myocyte directional growth; 2) to perform a mechanistic interrogation of ERK1/2 targets as effectors of directional myocyte growth, and 3) to define the role of MEK1-ERK1/2 signaling in regulating myocyte directional growth in genetic models of HCM and DCM.
The myocardium can hypertrophy in response to injury, changes in workload, or increases in wall stress, as well as due to genetic mutations in genes that encode sarcomeric proteins. In response to hypertrophic stimuli or tension alterations signaling pathways are activated that cause a fundamental reprogramming that results dimensional changes in myocyte growth. This application will attempt to identify novel effectors that mediate how the adult cardiac myocyte grows in width or length.
Showing the most recent 10 out of 31 publications
